Polymeric materials have been used for medical and surgical applications for 30 to 40 years and these applications often involved the use of the polymers in intimate contact with living tissues (Williams, Journal of Materials Science; (1982), 17:1233-1246). It has been stated that "the development of polymers containing hydrolytically or enzymatically labile bonds has been an ongoing activity for a very long time, principally in connection with a search for improved absorbable sutures. Although these sutures were originally derived almost exclusively from various forms of collagen and evolved to the modern day catgut, there has also been an increasing emphasis on developing synthetic materials that would hydrolyze to natural metabolites.
As a result of these efforts, two materials emerged, poly(lactic acid) and poly(glycolic acid) (Heller, material presented at the Massachusetts Institute of Technology Special Summer Program held Jul. 19 through Jul. 23, 1982). Since the first disclosure of the use of a synthetic biodegradable polymer for the systemic delivery of a therapeutic agent reported by Yolles, et al. (1970), a large body of literature has evolved which describes therapeutic agent release from bioerodible polymers. Three types of therapeutic agent release have been described which can occur from bioerodible polymers based on the mechanism of polymer erosion. These three types are designated as Type I, Type II and Type III erosion.
A Type I erosion system is composed of a water-soluble polymer which has been insolubilized by hydrolytically unstable crosslinks. The three-dimensional network of the system remains intact (insoluble) and can only swell to the extent allowed by the crosslink density when first placed in an aqueous environment. However, on prolonged contact with an aqueous environment, the crosslinks, which are hydrolytically labile, begin to cleave, the crosslink density decreases and the network will swell to the point where the majority of the crosslinks are broken and the matrix will dissolve. This type of system is very useful for the release of agents which have a very low water solubility and for macromolecules that can be physically entangled in the matrix. In this last case, the agents cannot diffuse out even though they are very water soluble. As a result, escape and dissolution of the agents can only take place after enough crosslinks have been cleaved to allow disentanglement of the macromolecule.
A Type II erosion system is composed of water-insoluble polymeric material which can be solubilized by hydrolysis, ionization, or protonation of a pendant group. Since the solubilization does not involve backbone cleavage, there is no significant change in molecular weight of the polymer as it is solubilized. Due to this fact, this type of system is useful for topical applications where the elimination of high molecular weight, water-soluble macromolecules is not a problem. This is not the case where this type of system is used internally as implant material because, in this situation, high molecular weight materials can cause elimination problems. The major use of this type of system has been in the field of enteric coatings where these coatings are designed to be soluble at specific pH's of the gastrointestinal tract.
A Type III erosion system is composed of hydrophobic polymers which are converted to small, water-soluble molecules by cleavage of hydrolytically labile bonds in the polymer backbone. In the past, the principle use of this type of system has been for the systemic administration of therapeutic agents from subcutaneous, intramuscular, or intraperitoneal implantation sites where the method of therapeutic agent delivery necessitates the use of polymers whose degradation products are nontoxic. Heller (Heller, material presented at the Massachusetts Institute of Technology Special Summer Program held Jul. 19 through Jul. 23, 1982)) stated that systems based on this type of erosion are being developed along four parallel approaches. These include: (a) diffusional systems in which the rate-limiting barrier membrane will ultimately erode; (b) bioerodible microcapsules; (c) monolithic devices containing dispersed or dissolved therapeutic agent; and (d) bioerodible polymers containing therapeutic agents chemically bound to the polymer backbone.
This last class of bioerodable system was described by Kopachek et al. (1983, Prog. Polym. Sci., 9:1-58) in an article reviewing the biodegradation of various biomedical polymers. The author reviews the work of others in the field who use polylactic acid as the polymer of choice. The rate of polymer degradation and drug release is controlled through chemical modification of the particular polymer(s) used as well as the ratio of included polymers one to another. However, the use of an extrinsic enzyme in or on the polymer device was not introduced to further control or enhance a linear rate of drug release from the polymer. While erosion rate modifiers, such as those disclosed by Schmidt et al. (U.S. Pat. No. 4,346,709), have been used in conjunction with polymeric devices to decrease the rate of drug delivery, the inclusion of a "modifier", for example an enzyme, has not been proposed to enhance the rate of drug release.
Others in the art have discussed the ability of naturally occurring enzymes to degrade polymeric substances (Williams, D. F. (1980), Eng. Med., 10:5-7). For example, Williams described the enzymatic degradation of polylactic acid by various enzymes, including bromelain, esterase, ficin, lactate dehydrogenase, pronase and proteinase K (Id. at 6). However, the inclusion of a therapeutic agent in such a system was not addressed. The inclusion of a therapeutic agent in a polymeric substrate together with an enzyme was later examined by Langer and co-workers, but only in reference to the cleavage of drug-polymer bonds in a "pendant" chain system (Langer, A. (1980) Chem. Eng. Commun., 6:1-48). This system required that the cleavage of the drug from the polymer backbone be the rate-limiting step in order that a constant release of the drug from the polymer be achieved (Id. at 33). Such would require that the rate of diffusion of the enzyme and the rate of diffusion of the drug be faster than the rate of drug-polymer cleavage by the enzyme (Id.). This particular system limited the use of therapeutic agents to those "bindable" ( i.e., those with particular conformational and/or structural characteristics) to a polymeric substrate. The use of enzymes in conjunction with unbound therapeutic agents in a polymeric slab, however, remained unexplored.
The present invention comprises a type III erosion system. However, the therapeutic agent of the present invention is not bound to the polymer backbone of the bioerodable polymer. In one well-characterized example, a monolithic system based on the use of poly(DL-lactide), a polymeric material that undergoes bulk degradation, is disclosed. The physically entrapped therapeutic agent included in the polymer is released as the enzyme is activated by moisture. The moisture-activated enzyme then degrades the polymeric slab, thus releasing the physically entrapped therapeutic agent. Release of the therapeutic agent is thus controlled by a combination of diffusion and erosion.
An objective of the present invention is to develop a slab of therapeutic agent-containing polymer which will release therapeutic agent at a relatively constant rate, the rate being affected by the enzymatic cleavage of the polymer by a preferred enzyme. The enzyme thus acts to internally control the physical release at a constant rate of unbound homogeneously-dispersed therapeutic agent from the polymeric structure in which it is contained.
As will be appreciated, the present invention is not taught or suggested by the art in general or the above described references. Particularly, the references do not address the specific inclusion of a moisture-activated enzyme in a polymeric device itself to enhance the rate of therapeutic drug delivery, such as the device described by Kopachek, Schmidt and Williams. While Langer et al. describes an enzyme and polymer-bound drug delivery system, the art is void of any suggestion or teaching of a polymeric device with a non-polymer bound therapeutic agent and moisture-activated enzyme. The present system thus is not limited to therapeutic agents with structural characteristics suitable for binding to a polymeric substrate, and further features a therapeutic agent release rate independent of the rate at which drug-polymer bonds are enzymatically cleaved. This limitation as described in regard to the device of Langer et al. has been overcome by Applicants' with a system which physically entraps the therapeutic agent, without polymer bonding, the polymeric structure of the device.